Every year more than 12 million people are diagnosed with cancer worldwide and over 7.5 million people die from cancer each year. These numbers are expected to increase because of population growth and due to the lifestyle in the Western world. Radiotherapy is an important part of modern cancer treatment and more than 50% of cancer patients receive radiotherapy at least once. Modern radiotherapy relies on advanced high precision planning, treatment equipment and imaging techniques (such as, e.g., computed tomography (CT), positron-emission tomography (PET) and magnetic imaging resonance (MRI)) in order to deliver high radiation doses to a precisely defined target in patients.
One of the main difficulties in external beam radiotherapy is that both tumors and the surrounding tissue move significantly and unpredictably during radiotherapy; both within each single treatment, and during the whole course of radiotherapy, lasting usually 5-7 weeks. These movements can be dramatic (e.g. several cm within seconds) and may be caused by various factors such as respiration, bladder- and bowel filling, air passing colon, tumor shrinkage and set-up variation of the patient. One way of minimizing this problem is the implantation of markers in or adjacent to the tumor allowing frequent imaging and treatment adaptation. So far, markers have been inserted using long and thick needles, a complicated procedure with a significant risk of complications, which is limiting the practical usefulness of markers in radiotherapy.
Ideally, a tissue marker should enable tracking of tumor movement; be visible on several image modalities; be visible for an extended period (e.g., at least 4 weeks); be non-toxic; and be easy to insert.
WO 94/03155 A1 describes a hydrogel composition prepared from a backbone bonded to a cross-linking agent. The hydrogels may be loaded with therapeutic drugs and diagnostic labels, including x-ray contrast imaging agents for disease diagnostics and treatment.
WO 95/19184 A1 describes polymeric microparticles containing agents for imaging. The particles are prepared by cross-linking (ionotropically gelling) synthetic polyelectrolytes with multivalent ions such as calcium ions. The particles formed have sizes in the micrometer range.
U.S. 2008/0213189 A1 describes nanoparticles based on metal nanocrystals and having a graphitic shell, for use in imaging.
Couto et al. (Acta Biomater., 2009, 5, 115-123) describe a chitosan based thermo-responsive injectable hydrogel containing bioactive glass nanoparticles for bone tissue engineering applications.
Daniel-da-Silva et al. (Carbohydrate Polymers, 2012, 87, 328-335) describe a model drug-delivery system based on a K-carrageean hydrogel containing magnetic (FeO4) nanoparticles.
In view of the above, it is an object of the invention to provide new formulations comprising solid nano-sized particles and gel-forming, low-viscosity systems that are easy to administer parenterally, and wherein the solid particles that can be visualized by one or multiple imaging modalities, including X-ray imaging.